Papillomaviruses (PVs) infect the epithelia of animals and man, where they generally induce benign proliferation (warts or condylomata) at the site of infection. However, lesions induced by a subset of human papillomaviruses (HPVs), especially HPV16, can undergo malignant progression, and these HPVs cause cervical cancer and several other epithelial malignancies. Our current research is primarily concerned with development of vaccines and other infection inhibition strategies against HPV and elucidation of the HPV life cycle. We previously developed an efficient strategy for generating high titers of infectious papillomavirus particles that transduce encapsidated marker plasmids, designated pseudoviruses. Pseudovirus infection mimics the early steps in HPV infection and can therefore be used to study these events as well as interventions that may inhibit them. Our in vivo studies have also shown the pseudoviruses abrogate the strict species-specificity of authentic HPVs while retaining their epitheliotropism. These properties enabled us to develop the first cervicovaginal challenge model for HPVs. This system permits in vivo exploration of the steps involved in establishing infection. We have found that the infection of the female mouse genital tract, even of monolayer endocervical cells, requires binding of the virus to the basement membrane (BM), which can only occur following microtrauma sufficient to expose to the BM. The virions bind to heparan sulfated proteoglycans in the BM, as heparanase treatment prevents both BM binding and infection. The BM-bound virus undergoes an enzymatically mediated conformational change, leading to exposure of an epitope in the L2 minor capsid protein. Successful infection of epithelial cells only occurs after the BM-associated changes. Ongoing experiments are utilizing the in vivo system to study the mechanisms by which the current HPV vaccine prevents infection as well as to help develop second generation HPV vaccines. In collaboration with colleagues at Johns Hopkins, we have found that a candidate L2-based vaccine may have potential as a pan-HPV vaccine, as it can induce neutralization of a broad range of HPVs.